Acta Obstet Gynecol Scand 57: 281-285, 1978
TREATMENT OF MENOPAUSAL OESTROGEN DEFICIENCY SYMPTOMS IN HYSTERECTOMISED WOMEN BY MEANS OF 17P-OESTRADIOL PELLET IMPLANTS B. Staland From the Samariterhemmet Hospital, Gynecological Outpatient Department, Uppsala, Sweden
Abstract. Ninety-four women having undergone hysterectomy, with or without simultaneous ovariectomy, were treated for menopausal symptoms by means of subcutaneous implantation of sterile pellets containing 20 mg 17P-oestradio1, 589 implantations in all. The subjective effect was good and lasted generally for about 6 months. The Karyopyknotic index, serum FSH and plasma oestradiol were checked in a few of the patients. The method was judged to be valuable in appropriate cases.
17p-oestradiol-the most important of oestrogens occurring naturally in man-has long been used for treating menopausal symptoms, in the form of esters for injection and, in recent years, for oral use in esterified and free forms (1, 3, 4, 6, 8, 10). The use of oestradiol in the form of pellets for subparticular, implantation is not new. before long-acting oestradiol esters for injection became available, this method was used to a certain extent, but only on a small scale. There are only brief references to it in the literature. The author was able to find only one comprehensive study-that Of Mu11er (9). Chlorinda et (2)9 Stallworthy (13), Schleyer-Saunders (1 1) and Studd (14) mention the method without giving details of the patient sample. The patients in Miiller's investigation were mostly women with intact wombs. According to present knowledge of oestrogen treatment it is not surprising that bleeding occurred fairly frequently. The method is scarcely suitable for patients with uterus intact. Even with small amounts of oestrogens, bleeding readily occurs if the treatment is administered continuously for a long time. Furthermore continuous oestrogen treatment may possibly predispose patients to endometrial cancer. The implantation method should therefore be reserved for women who have undergone hyesterectomy. The author has used the
method on such Patients for more than 20 Years. The preparation used-Dimenformon compr. ad implantationem (depot t a b l e t s t w a s formerly registered in Sweden but over the last lCLl5 years has been Obtainable for licensed trial by courtesy Of N/V Organon. The sample discussed in this paper comprises all patients who have been accepted for treatment during the ten years from 1965 to 1975.
METHOD The preparation consists of compressed rod-shaped pellets containing 20 mg 17P-oestradiol without excipient. 2 mm in diameter and are 6 mm long. The pellets Each pellet is packed sterile in a vial. Their shape makes it easy to implant the pellet subcutaneously using a trocar and cannula. It also means that the surface area and therefore the absorption rate vary little during absorption period. Implantation is effected with a cannula with the Same inside diameter as the diameter of the pellet implant (2 mm) and provided with two trocars-one pointed for introducing the cannula and one blunt for inserting the pellet. The implantations were effected subcutaneously in the lower abdominal wall. The technique is extremely simple. After a little local anaesthetic has been injected intra- and subcutaneously, a small incision, 1-2 mm long, is made through the skin with a pointed scalpel blade. Through this the cannula with the pointed trocar is inserted 5-8 cm in the subcutaneous fat, nearly parallel to the skin, after which the implant pellet is inserted into the cannula and pushed in with the blunt trocar. No suture is required. With a little practice the whole procedure takes less than half a minute. No visible scar is left. Only at one single implantation did bleeding necessitate a suture. Occasionally minor, insignificant haematomas have appeared, but never any infection or other complication. Any discomfort is insignificant and patients who have also had hormone injections report that the implantations are less unpleasant than injections. When implanting in conjunction with laparotomy, the pellet may be inserted from the operation incision with a pair of tweezers into the subcutaneous fatty tissue. Acto Obstet Gvnecol Scand 57 (1978)
282
B . Staland
Table I. Duration of the effect on climacteric symptoms % of implant.
Duration (months)
No of implant.
0 4 4-5 5-6
2 19 104 254 49 80 81 589
6-7 7-8 8-
Undefined Total
with duration indicated (508)
0.4 3.7 20.5 50.0 9.7 15.7 100
PATIENTS The series consist of 94 patients, all of whom had undergone hysterectomy-in most cases total-including 46 with simultaneous bilateral ovariectomy. For 15 of the patiens, the first implantation was effected in conjunction with the operation, for the others from less than 1 year to 29 years afterwards. The ages at the start of treatment ranged from 38 to 72. The indications for treatment were, in the first instance, typical menopausal disorders in the form of sweating and hot flushes. Less continuous symptoms such as headache, palpitation, muscular pains, insomnia and various mental symptoms often occurred simultaneously. In some older patients the symptoms of sweating and hot flushes were insignifcant or completely absent. The indication for treatment was here primarily urogenital symptoms such as vaginal atrophy with symptoms of so-called senile colpitis, dysuria and urgency incontinence, together with difficulties in resuming sexual relations. Even in milder cases of stress incontinence, the treatment was of some value. The series includes altogether 589 implantations. The number of implantations in cases where the effect could be studied was between 2 and 38-for 61 patients at least 5 and for 26 patients at least 10 implantations.
RESULTS The assessment of the effect was based primarily on information given by the patients themselves. The subjective effect was very good throughout. Only 2 patients reported an unsatisfactory effect on sweating and hot flushes. Many patients had previously various forms of oestrogen treatment and practically all preferred the implantation method. The patients also included an appreciable number who had previously been treated with sedatives and similar preparations without any effect whatsoever. It is often stated that the placebo effect when treating menopausal symptoms is high. Figures up to 35% have been indicated (5). This does not tally Artu Obstet Gynrcol Srand 57 (1978)
with the author’s own experience, nor with more recent investigations. Lauritzen (6) indicates a figure of 10-13%. The very poor effect of sedatives in itself constitutes evidence against a very high degree of placebo effect. No direct comparison with placebo could be made in the present investigation, though some efforts in this direction were made, however. Thus when implantation was effected at the same time as a bilateral ovariectomy, the patients were not informed about implantation but were asked to report if any climacteric symptoms appeared. The duration of effect for this first implant is the same as that for the patients as a whole. The mean duration for implantation in conjunction with operation was 5.9f0.03 months, For all cases together it was 6.1k0.05 months. Difference 0.2k0.3 months. Presumably the absorption time would be curtailed if the pellet was fragmented, and this was, in fact, observed when it was unintentionally broken during implantation. This seemed to afford a chance to determine to what extent the patient’s idea of the effective duration might be influenced by the check-up being usually arranged for 6 months later. In 21 cases selected at random, the pellet was deliberately broken into 2-3 pieces before being implanted. This was not recorded in the notes, so that the doctor should not unintentionally lead the patient when asking about the duration of the effect. The notes concerning fragmentation were not taken out until we went through the material for processing it. This showed, as anticipated, that the interval before the disorders returned was, indeed, shorter than usual. It varied between 4 and 6 months with an average of 5.2k0.15 months compared with 6.1 f0.05 months for the whole sample. The difference was 0.9k0.16 months and therefore statistically significant. Table I shows the duration of the subjective effect. As a rule the patients were treated again after 6 months. This period was modified in individual cases according to the duration of the effect. The patients were requested to note the time of onset of sweating and flushes and were usually given a prescription for some oral oestrogen preparation to take when necessary. Only in exceptional cases did they need to avail themselves of this. The effective durations indicated in the table are to be regarded as minimum ones as those patients who, upon return and further implantation, had not always had a recurrence of symptoms at that time. Thus “6-7
17P-oestradiol pellet implants
283
Table 11. Objective parameters Before treatment
3 months
6 months
Determin.
YariaNo. tion Mean
VariaNo. tion Mean
VariaNo. tion Mean
K1,%
6
0-10
2.0
6
35-66
46.1
6
1040
18.5
Months Difference
0-3 0-6
FSH , LLdl
5
E2,pmol/l
3
6.7-15 10.5k1.7
37-92
56.3k21.8
10
7
0.4-9.2
3. k l . 0
16
69-330 195. k34.1 15
3-6 0-3 0-6 3-6 5%242 152.5f14.7 6 3 0.5-14
4.1k0.8
0-6
3-6
**
44.1 *** 16.5** -27.6** 6.8k2.0 6.4f2.4 0.4k1.3 138.8f40.5 %.2?26.3 42.6f37.1
t-Testp
TREATMENT OF MENOPAUSAL OESTROGEN DEFICIENCY SYMPTOMS IN HYSTERECTOMISED WOMEN BY MEANS OF 17P-OESTRADIOL PELLET IMPLANTS B. Staland From the Samariterhemmet Hospital, Gynecological Outpatient Department, Uppsala, Sweden
Abstract. Ninety-four women having undergone hysterectomy, with or without simultaneous ovariectomy, were treated for menopausal symptoms by means of subcutaneous implantation of sterile pellets containing 20 mg 17P-oestradio1, 589 implantations in all. The subjective effect was good and lasted generally for about 6 months. The Karyopyknotic index, serum FSH and plasma oestradiol were checked in a few of the patients. The method was judged to be valuable in appropriate cases.
17p-oestradiol-the most important of oestrogens occurring naturally in man-has long been used for treating menopausal symptoms, in the form of esters for injection and, in recent years, for oral use in esterified and free forms (1, 3, 4, 6, 8, 10). The use of oestradiol in the form of pellets for subparticular, implantation is not new. before long-acting oestradiol esters for injection became available, this method was used to a certain extent, but only on a small scale. There are only brief references to it in the literature. The author was able to find only one comprehensive study-that Of Mu11er (9). Chlorinda et (2)9 Stallworthy (13), Schleyer-Saunders (1 1) and Studd (14) mention the method without giving details of the patient sample. The patients in Miiller's investigation were mostly women with intact wombs. According to present knowledge of oestrogen treatment it is not surprising that bleeding occurred fairly frequently. The method is scarcely suitable for patients with uterus intact. Even with small amounts of oestrogens, bleeding readily occurs if the treatment is administered continuously for a long time. Furthermore continuous oestrogen treatment may possibly predispose patients to endometrial cancer. The implantation method should therefore be reserved for women who have undergone hyesterectomy. The author has used the
method on such Patients for more than 20 Years. The preparation used-Dimenformon compr. ad implantationem (depot t a b l e t s t w a s formerly registered in Sweden but over the last lCLl5 years has been Obtainable for licensed trial by courtesy Of N/V Organon. The sample discussed in this paper comprises all patients who have been accepted for treatment during the ten years from 1965 to 1975.
METHOD The preparation consists of compressed rod-shaped pellets containing 20 mg 17P-oestradiol without excipient. 2 mm in diameter and are 6 mm long. The pellets Each pellet is packed sterile in a vial. Their shape makes it easy to implant the pellet subcutaneously using a trocar and cannula. It also means that the surface area and therefore the absorption rate vary little during absorption period. Implantation is effected with a cannula with the Same inside diameter as the diameter of the pellet implant (2 mm) and provided with two trocars-one pointed for introducing the cannula and one blunt for inserting the pellet. The implantations were effected subcutaneously in the lower abdominal wall. The technique is extremely simple. After a little local anaesthetic has been injected intra- and subcutaneously, a small incision, 1-2 mm long, is made through the skin with a pointed scalpel blade. Through this the cannula with the pointed trocar is inserted 5-8 cm in the subcutaneous fat, nearly parallel to the skin, after which the implant pellet is inserted into the cannula and pushed in with the blunt trocar. No suture is required. With a little practice the whole procedure takes less than half a minute. No visible scar is left. Only at one single implantation did bleeding necessitate a suture. Occasionally minor, insignificant haematomas have appeared, but never any infection or other complication. Any discomfort is insignificant and patients who have also had hormone injections report that the implantations are less unpleasant than injections. When implanting in conjunction with laparotomy, the pellet may be inserted from the operation incision with a pair of tweezers into the subcutaneous fatty tissue. Acto Obstet Gvnecol Scand 57 (1978)
282
B . Staland
Table I. Duration of the effect on climacteric symptoms % of implant.
Duration (months)
No of implant.
0 4 4-5 5-6
2 19 104 254 49 80 81 589
6-7 7-8 8-
Undefined Total
with duration indicated (508)
0.4 3.7 20.5 50.0 9.7 15.7 100
PATIENTS The series consist of 94 patients, all of whom had undergone hysterectomy-in most cases total-including 46 with simultaneous bilateral ovariectomy. For 15 of the patiens, the first implantation was effected in conjunction with the operation, for the others from less than 1 year to 29 years afterwards. The ages at the start of treatment ranged from 38 to 72. The indications for treatment were, in the first instance, typical menopausal disorders in the form of sweating and hot flushes. Less continuous symptoms such as headache, palpitation, muscular pains, insomnia and various mental symptoms often occurred simultaneously. In some older patients the symptoms of sweating and hot flushes were insignifcant or completely absent. The indication for treatment was here primarily urogenital symptoms such as vaginal atrophy with symptoms of so-called senile colpitis, dysuria and urgency incontinence, together with difficulties in resuming sexual relations. Even in milder cases of stress incontinence, the treatment was of some value. The series includes altogether 589 implantations. The number of implantations in cases where the effect could be studied was between 2 and 38-for 61 patients at least 5 and for 26 patients at least 10 implantations.
RESULTS The assessment of the effect was based primarily on information given by the patients themselves. The subjective effect was very good throughout. Only 2 patients reported an unsatisfactory effect on sweating and hot flushes. Many patients had previously various forms of oestrogen treatment and practically all preferred the implantation method. The patients also included an appreciable number who had previously been treated with sedatives and similar preparations without any effect whatsoever. It is often stated that the placebo effect when treating menopausal symptoms is high. Figures up to 35% have been indicated (5). This does not tally Artu Obstet Gynrcol Srand 57 (1978)
with the author’s own experience, nor with more recent investigations. Lauritzen (6) indicates a figure of 10-13%. The very poor effect of sedatives in itself constitutes evidence against a very high degree of placebo effect. No direct comparison with placebo could be made in the present investigation, though some efforts in this direction were made, however. Thus when implantation was effected at the same time as a bilateral ovariectomy, the patients were not informed about implantation but were asked to report if any climacteric symptoms appeared. The duration of effect for this first implant is the same as that for the patients as a whole. The mean duration for implantation in conjunction with operation was 5.9f0.03 months, For all cases together it was 6.1k0.05 months. Difference 0.2k0.3 months. Presumably the absorption time would be curtailed if the pellet was fragmented, and this was, in fact, observed when it was unintentionally broken during implantation. This seemed to afford a chance to determine to what extent the patient’s idea of the effective duration might be influenced by the check-up being usually arranged for 6 months later. In 21 cases selected at random, the pellet was deliberately broken into 2-3 pieces before being implanted. This was not recorded in the notes, so that the doctor should not unintentionally lead the patient when asking about the duration of the effect. The notes concerning fragmentation were not taken out until we went through the material for processing it. This showed, as anticipated, that the interval before the disorders returned was, indeed, shorter than usual. It varied between 4 and 6 months with an average of 5.2k0.15 months compared with 6.1 f0.05 months for the whole sample. The difference was 0.9k0.16 months and therefore statistically significant. Table I shows the duration of the subjective effect. As a rule the patients were treated again after 6 months. This period was modified in individual cases according to the duration of the effect. The patients were requested to note the time of onset of sweating and flushes and were usually given a prescription for some oral oestrogen preparation to take when necessary. Only in exceptional cases did they need to avail themselves of this. The effective durations indicated in the table are to be regarded as minimum ones as those patients who, upon return and further implantation, had not always had a recurrence of symptoms at that time. Thus “6-7
17P-oestradiol pellet implants
283
Table 11. Objective parameters Before treatment
3 months
6 months
Determin.
YariaNo. tion Mean
VariaNo. tion Mean
VariaNo. tion Mean
K1,%
6
0-10
2.0
6
35-66
46.1
6
1040
18.5
Months Difference
0-3 0-6
FSH , LLdl
5
E2,pmol/l
3
6.7-15 10.5k1.7
37-92
56.3k21.8
10
7
0.4-9.2
3. k l . 0
16
69-330 195. k34.1 15
3-6 0-3 0-6 3-6 5%242 152.5f14.7 6 3 0.5-14
4.1k0.8
0-6
3-6
**
44.1 *** 16.5** -27.6** 6.8k2.0 6.4f2.4 0.4k1.3 138.8f40.5 %.2?26.3 42.6f37.1
t-Testp
